DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

antagonists are in development and a few have been
approved for clinical use. Anakinra is an FDAapproved
recombinant, non-glycosylated form of
human IL-1RA for the management of joint disease
in rheumatoid arthitis. It can be used alone or in combination
with anti-TNF agents such as etanercept
(ENBREL), infliximab (REMICADE), or adalimumab
(HUMIRA). Canakinumab (ILARIS) is an IL-1β monoclonal
antibody approved by the FDA in June 2009 for
Cryoprin-associated periodic syndromes (CAPS), a
group of rare inherited inflammatory diseases associated
with overproduction of IL-1 that includes
Familial Cold Autoinflammatory and Muckle-Wells
Syndromes (Lachmann et al., 2009). Canakinumab is
also being evaluated for use in chronic obstructive pulmonary
disease (Church et al., 2009). Rilonacept (IL-1
TRAP) is another IL-1 blocker (a fusion protein that
binds IL-1) that is now being evaluated in a phase 3
study for gout (Terkeltaub et al., 2009). IL-1 is an
inflammatory mediator of joint pain associated with
elevated uric acid crystals.
Lymphocyte Function–Associated
Antigen-1 (LFA-1) Inhibition
Efalizumab. (RAPTIVA) is a humanized IgG 1
mAb targeting
the CD11a chain of lymphocyte function–associated
antigen-1 (LFA-1). Efalizumab binds to LFA-1 and prevents
the LFA-1–intercellular adhesion molecule
(ICAM) interaction to block T-cell adhesion, trafficking,
and activation.
Pretransplant therapy with anti-CD11a prolonged survival of
murine skin and heart allografts and monkey heart allografts (Nakakura
et al., 1996). A randomized, multicenter trial of a murine anti–ICAM-
1 mAb (enlimomab) failed to reduce the rate of acute rejection or to
improve delayed graft function of cadaveric renal transplants (Salmela
et al., 1999). This may have been due to either the murine nature of the
mAb or the redundancy of the ICAMs. Efalizumab also is approved
for use in patients with psoriasis. In a phase I/II open-label, dose-ranging,
multidose, multicenter trial, efalizumab (dose, 0.5 mg/kg or 2
mg/kg) was administered subcutaneously for 12 weeks after renal transplantation
(Vincenti et al., 2001; Vincenti et al., 2007). Both doses of
efalizumab decreased the incidence of acute rejection. Pharmacokinetic
and pharmacodynamic studies showed that efalizumab produced saturation
and 80% modulation of CD11a within 24 hours of therapy. In a
subset of 10 patients who received the higher dose efalizumab (2
mg/kg) with full-dose cyclosporine, MMF, and steroids, three patients
developed post-transplant lymphoproliferative diseases. Progressive
multifocal leukoencephalopathy (PML) also has occurred during therapy
with efalizumab. Although efalizumab appears to be an effective
immunosuppressive agent, it may be best used in a lower dose and with
an immunosuppressive regimen that spares calcineurin inhibitors.
Several trials are being conducted with efalizumab in renal, liver, and
islet cell transplantation.
Alefacept
(AMEVIVE) is a human LFA-3-IgG1 fusion protein. The
LFA-3 portion of alefacept binds to CD2 on T lymphocytes,
blocking the interaction between LFA-3 and CD2
and interfering with T-cell activation. Alefacept is FDA
approved for use in psoriasis.
Treatment with alefacept has been shown to produce a dosedependent
reduction in T-effector memory cells (CD45, RO+) but
not in naïve cells (CD45, RA+). This effect has been related to its
efficacy in psoriatic disease and is of significant interest in transplantation
because T-effector memory cells have been associated
with co-stimulation blockade resistant and depletional inductionresistant
rejection. Alefacept will delay rejection in non-human
primate (NHP) cardiac transplantation and has recently been shown
to have synergistic potential when used with co-stimulation blockade
and/or sirolimus-based regimens in NHPs (Vincenti and Kirk,
2008). A phase II randomized, open-label, parallel-group, multicenter
study to assess the safety and efficacy of maintenance therapy
with alefacept in kidney transplant recipients currently is under way.
Targeting B Cells
Most of the advances in transplantation can be attributed
to drugs designed to inhibit T-cell responses. As a
result, T cell–mediated acute rejection has been become
much less of a problem, while B cell–mediated
responses such as antibody-mediated rejection and
other effects of donor-specific antibodies have become
more evident. Thus, several agents, both biologicals and
small molecules with B-cell specific effects now are
being considered for development in transplantation,
including humanized monoclonal antibodies to CD20
and inhibitors of the two B cell–activation factors
BLYS and APRIL and their respective receptors.
TOLERANCE
Immunosuppression has concomitant risks of opportunistic
infections and secondary tumors. Therefore, the
ultimate goal of research on organ transplantation and
auto-immune diseases is to induce and maintain
immunological tolerance, the active state of antigenspecific
nonresponsiveness (Krensky and Clayberger,
1994). Tolerance, if attainable, would represent a true
cure for conditions discussed earlier in this section without
the side effects of the various immunosuppressive
therapies. The calcineurin inhibitors prevent tolerance
induction in some, but not all, preclinical models (Van
Parijs and Abbas, 1998). In these same model systems,
sirolimus does not prevent tolerance and may even promote
tolerance induction (Li et al., 1998). Several other
promising approaches are being evaluated in clinical
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS